CRISPR-Cas9-mediated therapeutic editing of Rpe65 ameliorates the disease phenotypes in a mouse model of Leber congenital amaurosis

Leber congenital amaurosis (LCA), one of the leading causes of childhood-onset blindness, is caused by autosomal recessive mutations in several genes including . In this study, we performed CRISPR-Cas9-mediated therapeutic correction of a disease-associated nonsense mutation in in mice, a model of h...

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Published inScience advances Vol. 5; no. 10; p. eaax1210
Main Authors Jo, Dong Hyun, Song, Dong Woo, Cho, Chang Sik, Kim, Un Gi, Lee, Kyu Jun, Lee, Kihwang, Park, Sung Wook, Kim, Daesik, Kim, Jin Hyoung, Kim, Jin-Soo, Kim, Seokjoong, Kim, Jeong Hun, Lee, Jung Min
Format Journal Article
LanguageEnglish
Published United States American Association for the Advancement of Science 01.10.2019
Subjects
Animals
Cell Biology
cis-trans-Isomerases - genetics
cis-trans-Isomerases - metabolism
CRISPR-Cas Systems - genetics
Dependovirus - metabolism
Disease Models, Animal
Gene Editing
Genome
Health and Medicine
Human Genetics
Leber Congenital Amaurosis - genetics
Leber Congenital Amaurosis - therapy
Male
Mice
Mice, Inbred C57BL
Mutation - genetics
Phenotype
Recombinational DNA Repair
Retina - pathology
Retina - physiopathology
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Summary:Leber congenital amaurosis (LCA), one of the leading causes of childhood-onset blindness, is caused by autosomal recessive mutations in several genes including . In this study, we performed CRISPR-Cas9-mediated therapeutic correction of a disease-associated nonsense mutation in in mice, a model of human LCA. Subretinal injection of adeno-associated virus carrying CRISPR-Cas9 and donor DNA resulted in >1% homology-directed repair and ~1.6% deletion of the pathogenic stop codon in in retinal pigment epithelial tissues of mice. The a- and b-waves of electroretinograms were recovered to levels up to 21.2 ± 4.1% and 39.8 ± 3.2% of their wild-type mice counterparts upon bright stimuli after dark adaptation 7 months after injection. There was no definite evidence of histologic perturbation or tumorigenesis during 7 months of observation. Collectively, we present the first therapeutic correction of an nonsense mutation using CRISPR-Cas9, providing new insight for developing therapeutics for LCA.
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Present address: Seran Eye Center, Seoul, Republic of Korea.
These authors contributed equally to this work.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.aax1210